Abstract: Cancer is the second most common cause of death in the U.S.;over half a million Americans die from cancer each year. Despite the tremendous cancer research and treatment efforts over the past three decades, progress has been frustratingly slow. A deeper understanding of fundamental tumor biology and innovative thinking are urgently needed. In this proposal, we focus on understanding a novel paradigm of tumorigenesis-the stress phenotype and stress-response addiction, which may represent a fundamental aspect of cancer biology and at the same time a principal vulnerability of cancer. Our previous findings reveal that the stress response, known to protect cells from stress, is also a multifaceted enabler of tumorigenesis. In a major advance from our original findings, this proposal aims to interrogate the role of a pioneering mechanism of the stress response- "genetic buffering" -in tumor evolution, and the potential clinical applications of the stress phenotype, an emerging hallmark of cancer. Specifically, we will address two key questions: 1) Can the stress response advance tumor evolution by genetic buffering? 2) Can the stress phenotype faithfully indicate tumor malignant potential? In addition to conceptual advances, this new paradigm could have broad clinical implications. The stress phenotype of cancer may be utilized as a generic indicator of tumor malignancy and a mechanism enabling an innovative approach for tumor molecular imaging. Further, because of the stress-response addiction of cancer, the stress response may serve as a novel target for both cancer prevention and therapy. In a broad sense, these concepts could provide a unifying framework for future cancer therapies. This proposed research is well suited to this unique funding mechanism, as it tests a newly emerging and highly innovative concept in cancer biology, which, if successful, could have major impacts on cancer research and treatment. Public Health Relevance: This research examines whether the stress response, which normally protects cells from environmental insults, actually enables, and may in fact be universally required for, cancer initiation and progression in human tumors. These pioneering studies may ultimately lead to development of the stress response as a general marker and target for novel diagnosis, prevention and treatment methods for human cancer.